Considerable interest has been shown in recent years in the use of prostaglandin (PG) precursors in medicine.
For various reasons it is not practical to administer naturally-occurring prostaglandins such as PGE 1 and PGE 2 to patients. Consequently, considerable attention has focussed on the use of prostaglandin precursors including linoleic acid, .gamma.-linolenic acid (GLA) and dihomo-.gamma.-linolenic acid (DGLA).
Conversion of these materials in the body is believed to be as shown in the following diagram.
The broad outline of this pathway is well known, but the details of control, inhibition and enhancement are shown as the present inventor believes them to operate. The pathway is now discussed with particular reference to treatment of inflammatory disorders according to the invention. This discussion is given in the belief that it elucidates the invention, but it is not intended that the invention should be limited by what is believed to be the reason for its effectiveness.
A major function of essential fatty acids (EFAs) is to act as precursors for prostaglandins (PGs), 1 series PGS being formed from dihomo-.gamma.-linolenic acid (DGLA) and 2 series PGs from arachidonic acid (AA). DGLA and AA are present in food in only small quantities, and the major EFA in food is linoleic acid which is first converted to .gamma.-linolenic acid (GLA) and then to DGLA and AA. The conversion of linoleic acid to GLA is blocked by a high fat and high carbohydrate diet, by ageing and by diabetes. Stores of AA in the body in the form of lipid esters are very large indeed. In contrast only small amounts of DGLA ester are present.
Thus the invention, in one aspect, serves to redress the 1-series PG depletion by administering .gamma.-linolenic acid and/or other materials tending to enhance 1-series PG production. In another aspect, desirably combined with the first, it seeks to restore TXA2 production directly.
It has further recently been found that a critical factor in some inflammatory disorders, e.g. in the damage of myelin which occurs in multiple sclerosis, may be the entry of calcium into cells. This may damage mitochondria and activate destructive lysosomal enzymes. Thus, there is now evidence which indicates that the regulation of the immune response and also the control of intracellular calcium may be significant factors in the treatment of various inflammatory disorders, e.g. multiple sclerosis, Crohn's disease and other disorders listed below.
The present inventor has now found that colchicine is a substance which appears to be able to potentiate the removal of calcium by cells and thus may be able to control intracellular calcium. Colchicine may also inhibit formation of 2 series PG's and enhance formation of 1 series PG's. In a further aspect of the invention, therefore, in conjunction with correction in EFA balance, colchicine is administered to effect such control. The relationship of this to EFA metabolism is discussed later.
In inflammatory disorders, production of 2 series PGs from arachidonic acid is greatly exaggerated. In inflammatory disorders these PGs are thought to contribute to the causation of the disease because steroids and aspirin-like drugs are both partially effective therapies, steroids blocking the conversion of AA esters to free AA and aspirin-like drugs blocking the conversion of free AA to endoperoxides which are intermediates in PG synthesis.
The overproduction of 2 series PGs implies that normal control of the PG synthetic pathway has been lost. Although control of this pathway is imperfectly understood two factors have been identified.
1. PGE1 is able to inhibit the formation of free AA from AA esters. This leads to the paradoxical fact that a partial EFA deficiency actually leads to increased formation of 2 series PGs, because DGLA stores are so much smaller than those of AA and a partial deficiency of EFAs will therefore lead to DGLA depletion first. This depletion will reduce formation of PGE1, remove the PGE1 control of AA and allow overproduction of 2 series PGs from the large AA stores. PA1 2. An unstable product of AA metabolism, thromboxane A2 (TXA2), also feeds back to inhibit conversion of AA ester to free AA and possibly also of free AA to PG2 endoperoxides. Thus loss of TXA2 will also lead to overproduction of 2 series PGs. TXA2 and PGE1 thus cooperate in the regulation of formation of 2 series PGs and a fault in the formation of either will lead to adnormalities. PA1 Penicillamine: 50 mg to 10 g/day PA1 Phenformin: 10 mg to 5 g/day PA1 Levamisole: 10 mg to 2 g/day PA1 amantadine: 100 to 1000 mg/day PA1 griseofulvin: 0.5 to 5 g/day PA1 vinblastine: 0.5 to 5 mg/kg/week (average weight 70 kg) PA1 vincristine: 0.1 to 1.0 mg/kg/week (average weight 70 kg) PA1 interferon (by injection): 1.times.10.sup.5 to 1.times.10.sup.8 units/day PA1 melatonin: 10 mg to 5 g/day
Thus for example the disorders of PG synthesis in inflammatory disorders can be accounted for by inadequate formation of PGE1 and/or TXA2.
The evidence for direct involvement of PGs in inflammatory disorders has been briefly mentioned. There is also indirect evidence that PGs may act by regulating--or failing to regulate--the calcium movements into and out of cells already mentioned above. The calcium concentration in cytoplasm is normally very low and there is now excellent evidence from many sources that a brief rise in cytoplasmic calcium concentration triggers a variety of cell events, including cell division and activation of lysosomes which contain destructive enzymes. Normally this calcium is very rapidly removed after this brief activation so terminating the event. PGs and related substances have specific actions on calcium and the present inventor has obtained evidence to suggest that TXA2 and PGF2.alpha. may be of critical importance. In particular, specific inhibition of TXA2 synthesis greatly prolongs the time taken for calcium to be removed from the cytoplasm after activation. Furthermore inhibition of TXA2 synthesis leads to increased formation of PGF.alpha. and PGE2 which can promote calcium entry into cells. There is thus good evidence that in this respect also PGE1 and TXA2 enhance one another's effects. In particular, in muscle the degree of contraction is related to the calcium concentration in the cytoplasm and muscle contraction is a measure of this calcium concentration. After inhibition of TXA2 synthesis the recovery from a contraction is greatly prolonged indicating slow removal of calcium. Further, inhibition of TXA2 synthesis can lead to a chronic state of partial contraction indicating the entry of calcium into the cytoplasm. PGF2.alpha. and PGE2 whose output is increased by inhibition of TXA2 synthesis also cause contraction indicating calcium entry into the cytoplasm.
Thus loss of TXA2 and PGE1 synthesis will lead to increased formation of 2 series PGs and entry of calcium into the cytoplasm. This calcium may activate cell division and also activate lysosomes whose destructive enzymes may play a large part in inflammation.
On general grounds there are therefore reasons to suppose that suppression of excess production of 2 series PGs will have desirable effects in inflammatory disorders. Currently available conventional methods of suppression are administration of steroids and aspirin-like drugs. However, while these may suppress overproduction of 2 series PGs they will exaggerate further any deficiencies in PGs of the 1 series and in TXA2, which may explain why they control symptoms but do not usually alter the long term course of the disease.
The present invention proposes a radically new approach which will control excess PG2 series production by restoring towards normal, or enhancing, the formation of either or both of 1 series PGs and TXA2.
The methods proposed for doing this are as follows: